chr2-238329110-A-G

Variant names:

• chr2-238329110-A-G
• rs3769110
• NM_015650.4:c.683A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015650.4(TRAF3IP1):​c.683A>G​(p.Asn228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,550,390 control chromosomes in the GnomAD database, including 5,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N228N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1737 hom., cov: 31)
  • Exomes 𝑓: 0.054 (3393 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.658
• Publications: 10 publications found

Genes affected

TRAF3IP1 (HGNC:17861): (TRAF3 interacting protein 1) The protein encoded by this gene interacts with TNF receptor-associated factor 3, tethering it to cytoskeletal microtubules. The encoded protein is also an inhibitor of the innate type I IFN response. Defects in this gene are a cause of Senior-Loken syndrome 9. [provided by RefSeq, Mar 2017]

TRAF3IP1 Gene-Disease associations (from GenCC):

• Senior-Loken syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046848953).
• BP6: Variant 2-238329110-A-G is Benign according to our data. Variant chr2-238329110-A-G is described in ClinVar as Benign. ClinVar VariationId is 1167549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 17	1	NM_015650.4	ENSP00000362424.4
TRAF3IP1	ENST00000391993.7	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 15	1		ENSP00000375851.3
TRAF3IP1	ENST00000409739.2	n.*552A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000386648.2
TRAF3IP1	ENST00000409739.2	n.*552A>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000386648.2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17578 AN: 151526 Hom.: 1732 Cov.: 31

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0982

GnomAD2 exomes AF: 0.0810 AC: 12466 AN: 153818 AF XY: 0.0782

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0409

Gnomad OTH exome AF: 0.0702

GnomAD4 exome AF: 0.0541 AC: 75608 AN: 1398746 Hom.: 3393 Cov.: 31 AF XY: 0.0546 AC XY: 37684 AN XY: 690062

African (AFR) AF: 0.280 AC: 8795 AN: 31398

American (AMR) AF: 0.0768 AC: 2722 AN: 35426

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 1135 AN: 25142

East Asian (EAS) AF: 0.112 AC: 3994 AN: 35738

South Asian (SAS) AF: 0.0985 AC: 7802 AN: 79196

European-Finnish (FIN) AF: 0.103 AC: 5089 AN: 49306

Middle Eastern (MID) AF: 0.0991 AC: 559 AN: 5642

European-Non Finnish (NFE) AF: 0.0386 AC: 41610 AN: 1078916

Other (OTH) AF: 0.0673 AC: 3902 AN: 57982

GnomAD4 genome AF: 0.116 AC: 17609 AN: 151644 Hom.: 1737 Cov.: 31 AF XY: 0.118 AC XY: 8773 AN XY: 74120

African (AFR) AF: 0.267 AC: 11019 AN: 41216

American (AMR) AF: 0.0815 AC: 1243 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 164 AN: 3468

East Asian (EAS) AF: 0.102 AC: 526 AN: 5150

South Asian (SAS) AF: 0.113 AC: 537 AN: 4770

European-Finnish (FIN) AF: 0.113 AC: 1194 AN: 10532

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0394 AC: 2674 AN: 67944

Other (OTH) AF: 0.0972 AC: 205 AN: 2110

Alfa AF: 0.0683 Hom.: 1501

Bravo AF: 0.120

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.234 AC: 975

ESP6500EA AF: 0.0362 AC: 298

ExAC AF: 0.0443 AC: 3961

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRAF3IP1-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.24
DEOGEN2	Benign	0.0048	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.60	N;N
PhyloP100		0.66
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.033
Sift	Benign	0.42	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;B
Vest4		0.026
MPC		0.11
ClinPred		0.0012	T
GERP RS		-0.82
Varity_R		0.013
gMVP		0.026
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3769110; hg19: chr2-239237751;